Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase
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Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase. / Langer, Florian; Spath, Brigitte; Fischer, Cornelia; Stolz, Moritz; Ayuketang, Francis Ayuk; Kröger, Nicolaus-Martin; Bokemeyer, Carsten; Ruf, Wolfram.
in: BLOOD, Jahrgang 121, Nr. 12, 21.03.2013, S. 2324-35.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase
AU - Langer, Florian
AU - Spath, Brigitte
AU - Fischer, Cornelia
AU - Stolz, Moritz
AU - Ayuketang, Francis Ayuk
AU - Kröger, Nicolaus-Martin
AU - Bokemeyer, Carsten
AU - Ruf, Wolfram
PY - 2013/3/21
Y1 - 2013/3/21
N2 - Lymphocyte depletion with antithymocyte globulin (ATG) can be complicated by systemic coagulation activation. We found that ATG activated tissue factor procoagulant activity (TF PCA) on monocytic cells more potently than other stimuli that decrypt TF, including cell disruption, TF pathway inhibitor inhibition, and calcium ionophore treatment. Induction of TF PCA by ATG was dependent on lipid raft integrity and complement activation. We showed that ATG-mediated TF activation required complement activation until assembly of the C5b-7 membrane insertion complex, but not lytic pore formation by the membrane attack complex C5b-9. Consistently, induction of TF PCA by ATG did not require maximal phosphatidylserine membrane exposure and was not correlated with the magnitude of complement-induced lytic cell injury. Blockade of free thiols, an inhibitory monoclonal antibody to protein disulfide isomerase (PDI), and the small-molecule PDI antagonist quercetin-3-rutinoside prevented ATG-mediated TF activation, and C5 complement activation resulted in oxidation of cell surface PDI. This rapid and potent mechanism of cellular TF activation represents a novel connection between the complement system and cell surface PDI-mediated thiol-disulfide exchange. Delineation of this clinically relevant mechanism of activation of the extrinsic coagulation pathway during immunosuppressive therapy with ATG may have broader implications for vascular thrombosis associated with inflammatory disorders.
AB - Lymphocyte depletion with antithymocyte globulin (ATG) can be complicated by systemic coagulation activation. We found that ATG activated tissue factor procoagulant activity (TF PCA) on monocytic cells more potently than other stimuli that decrypt TF, including cell disruption, TF pathway inhibitor inhibition, and calcium ionophore treatment. Induction of TF PCA by ATG was dependent on lipid raft integrity and complement activation. We showed that ATG-mediated TF activation required complement activation until assembly of the C5b-7 membrane insertion complex, but not lytic pore formation by the membrane attack complex C5b-9. Consistently, induction of TF PCA by ATG did not require maximal phosphatidylserine membrane exposure and was not correlated with the magnitude of complement-induced lytic cell injury. Blockade of free thiols, an inhibitory monoclonal antibody to protein disulfide isomerase (PDI), and the small-molecule PDI antagonist quercetin-3-rutinoside prevented ATG-mediated TF activation, and C5 complement activation resulted in oxidation of cell surface PDI. This rapid and potent mechanism of cellular TF activation represents a novel connection between the complement system and cell surface PDI-mediated thiol-disulfide exchange. Delineation of this clinically relevant mechanism of activation of the extrinsic coagulation pathway during immunosuppressive therapy with ATG may have broader implications for vascular thrombosis associated with inflammatory disorders.
KW - Antilymphocyte Serum
KW - Cells, Cultured
KW - Complement Activation
KW - Complement C5
KW - Disulfides
KW - Drug Evaluation, Preclinical
KW - Humans
KW - Membrane Microdomains
KW - Models, Biological
KW - Monocytes
KW - Oxidation-Reduction
KW - Protein Disulfide-Isomerases
KW - Thromboplastin
KW - Time Factors
U2 - 10.1182/blood-2012-10-460493
DO - 10.1182/blood-2012-10-460493
M3 - SCORING: Journal article
C2 - 23315166
VL - 121
SP - 2324
EP - 2335
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 12
ER -